This is a proposal to identify the chromosomal location of genes responsible for Tourette Syndrome (TS), an inherited disorder characterized by motor and vocal tics. They plan studies of two genetically homogeneous populations that have expanded rapidly over the past few hundred years: that of the Central Valley of Costa Rica (CR) and that of Ashkenazi Jews in the United States. TS patients in these populations may have inherited a susceptibility to this disorder from one or a few common ancestors. TS genes will be mapped by searching for genomic regions that TS patients share identical by descent (IBD) from such ancestors; these regions will include the TS genes, and may differ between the two populations. They will search for IBD regions by randomly sampling only affected individuals and their parents from these isolated populations. The study sample will consist of individuals moderately to severely affected with TS, about 100 from CR and about 200 Ashkenazim. Diagnostic assessment will include interviews of patients and family members and review of medical records; final diagnoses will be assigned through a 'best estimate' consensus process conducted by experts in diagnosing TS. Genealogies will be obtained for all subjects, who will be included in the study only if most of their ancestors were from the target populations. The samples will be genotyped using markers distributed throughout the genome. Evaluation of IBD in each genome region will be accomplished using association tests. Their computer simulation power studies show a high probability of detecting TS loci in each study population, even if TS is etiologically heterogeneous within each population. Once TS genes are localized, fine-mapping studies will begin, leading to positional cloning efforts. Also, clinical questions relevant to understanding the cause and course of TS will be addressed using the patients sampled for the PGM studies. They have completed preliminary studies to show the feasibility of the sampling, diagnostic, and genotyping approaches described in this proposal. The sampling will be facilitated by ongoing collaborations in CR and new collaborations with several TS centers in the U.S.